CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 760

Pgp inhibitor resulted in improved CNS accumulation, 174 , 180 modulation of Pgp
as well as BCRP activity can be a useful strategy to improve CNS penetration of
imatinib. 176 , 180
However, the safety of this approach should be explored carefully, as modulation
of Pgp in the blood-brain barrier may lead to increased CNS accumulation of un-
wanted potentially toxic xenobiotics and endogenous compounds. Preclinical studies
in wild-type mice and Mdr1a/b knockout mice demonstrated that Mdr1a/1b knock-
out mice are fertile and viable, but they are more sensitive than wild-type mice to
a range of drugs and toxins. 55 , 57 , 58 Moreover, absence or inhibition of Pgp activity
can alter the specific pharmacodynamic activity of some Pgp substrate drugs, leading
to CNS toxicity and adverse drug effects. For instance, the safe clinical use of the
antidiarrheal drug loperamide may also be critically dependent on the presence of
Pgp in the blood-brain barrier. Loperamide is a potent opiate which demonstrates
nearly exclusively peripheral opiatelike effects, on the gastrointestinal tract and no
central effects, because it is a Pgp substrate. Thus, normally, it cannot accumulate in
the CNS. In Mdr1a knockout mice, however, loperamide showed pronounced opiate-
like effects and sometimes lethal effects at doses that are safe in wild-type mice. 57 In
humans, coadministration of loperamide with the Pgp inhibitor quinidine produced
opiate-induced respiratory depression, a clear central opiate effect that is normally not
seen in humans. 181 Along the same line, blocking of placental Pgp in HIV-infected
pregnant women might be used to enhance HPI levels in the unborn child shortly
before and during delivery, thereby reducing the risk of HIV infection of the fetus.
However, the safety of this approach needs to be studied in greater detail. For instance,
preclinical data using Mdr1a/1b knockout mice demonstrated significantly increased
fetal penetration of the HPIs indinavir and saquinavir, indicating that placental Pgp
might have a protective role for the fetus. 66 , 167
24.2.2. ABCG2 (BCRP)
Impact of Polymorphism on Function Currently, more than 80 naturally occurring
SNPs in the BCRP gene have been identified with different ethnic distribution. 182 - 186
Few commonly occurring SNPs with presumed clinical consequences have been
studied: the G34A (V12M, replacing valine by methionine), C376T (with a stop
codon for glutamine 126), and C421A (Q141K, a transversion changing glutamine
to lysine at codon 141). 183 Recently, 19 ABCG2 SNPs were found in a Dutch pop-
ulation, of which seven were unknown previously. 186 The Q141K polymorphism
located in exon 5 showed an allele frequency ranging between 1 and 35%, with the
highest allele frequencies in Japanese and Chinese populations and rare detection
in African and African-American subjects. 185 , 187 In vitro functional characterization
and in vivo protein expression in human tissue samples of certain ABCG2 allelic
variants (e.g., V12M, Q141K, C34A) have been performed, but contradicting results
were reported. 183 , 185 , 188 - 190 However, a recent clinical study has documented a cor-
relation between Q141K polymorphism and significant pharmacokinetics changes of
the BCRP substrate diflomotecan when administered intravenously, suggesting that